The present invention relates to the development of hydrogel polymer compositions that are non-degradable, low-swelling and initially water soluble. More specifically, the hydrogel polymer compositions may be formed in situ and are useful as, e.g., embolic materials, bulking agents, and inflation or support media for certain types of medical devices. The present invention additionally includes a kit for preparing the hydrogel polymer compositions.
Hydrogel polymers are cross-linked hydrophilic macromolecules which have use in medical applications. While much progress has been made in such applications, further developments are needed to optimize the physical and mechanical properties of these materials for particular in vivo applications as described below.
One exemplary application for the hydrogel polymer materials discussed herein is as an inflation or support media for inflatable intraluminal grafts or stent grafts. Examples of such inflatable stent grafts are described in commonly owned U.S. Pat. No. 6,395,019 to Chobotov, pending U.S. patent application Ser. No. 10/384,103 to Kari et al. entitled “Kink-Resistant Endovascular Graft”, filed Mar. 6, 2003, and U.S. patent application Ser. No. 10/327,711 to Chobotov et al., entitled “Advanced Endovascular Graft”, filed Dec. 20, 2002, the entirety of each of which is incorporated herein by reference. These documents describe a stent graft in which additional structural integrity to the device may be achieved by the introduction of a polymeric fill material to channels and cuffs located on the graft portion so to act as a graft inflation and support medium.
Ideally, the inflation or support medium used in the stent grafts described above is biocompatible, has a cure time from about a few minutes to tens of minutes, exhibits minimal volumetric shrinking and swelling as it cures, exhibits long-term stability (preferably for at least ten years in vivo), poses as little an embolic risk as possible in the pre-cure state, and exhibits adequate mechanical properties, both in its pre- and post-cure states. For instance, such a material should have a relatively low viscosity before solidification or curing to facilitate the fill process into the stent graft.
Another application for the hydrogel polymers described herein is as a material for embolizing a body lumen such as a blood vessel or organ. Embolization, or the artificial blocking of fluid flow such as blood, may be used to treat a variety of maladies, including, by way of example only, controlling bleeding caused by trauma, preventing profuse blood loss during an operation requiring dissection of blood vessels, obliterating a portion of a whole organ having a tumor, blocking the blood flow into abnormal blood vessel structures such as aneurysms, arterio-venous malformations, arteriovenous fistulae, and blocking the passage of fluids or other materials through various body lumens. For such treatments, a variety of embolization technologies have been proposed, including for example mechanical means (including particulate technology), and liquid and semi-liquid technologies. The particular characteristics of such technologies (such as, e.g., the size of particles, radiopacity, viscosity, mechanism of occlusion, biological behavior and possible recanalization versus permanent occlusion, the means by which the material is delivered to the target body site, etc.), are factors used by the physician in determining the most suitable therapy for the indication to be treated.
Of the mechanical and particulate embolization technologies, the most prevalent include detachable balloons, macro- and microcoils, gelfoam and polyvinyl alcohol sponges (such as IVALON, manufactured and sold by Ivalon, Inc. of San Diego, Calif.), and microspheres. For example, one embolization technique uses platinum and stainless steel microcoils. However, significant expertise is required to choose a proper coil size for the malady prior to delivery. Moreover, many anatomical sites are not suitable for microcoils, and removal of microcoils has proved in certain circumstances difficult.
Liquid and semi-liquid embolic compositions include viscous occlusion gels, collagen suspensions, and cyanoacrylate (n-butyl and iso-butyl cyanoacrylates). Of these, cyanoacrylates have an advantage over other embolic compositions in their relative ease of delivery and in the fact that they are some of the only liquid embolic compositions currently available to physicians. However, the constituent cyanoacrylate polymers have the disadvantage of being biodegradable. Moreover, the degradation product, formaldehyde, is highly toxic to the neighboring tissues. See Vinters et al. “The histotoxicity of cyanoacrylate: A selective review”, Neuroradiology, 1985; 27:279-291. Another disadvantage of cyanoacrylate materials is that the polymer will adhere to body tissues and to the tip of the catheter. Thus, physicians must retract the catheter immediately after injection of the cyanoacrylate embolic composition or risk adhesion of the cyanoacrylate and the catheter to tissue such as blood vessels.
Another class of liquid embolic compositions is precipitative materials, which was invented in the late 1980's. See Sugawara et al., “Experimental investigations concerning a new liquid embolization method: Combined administration of ethanol-estrogen and polyvinyl acetate”, Neuro. Med. Chir. (Tokyo) 1993; 33:71-76; Taki et al., “A new liquid material for embolization of arterio-venous malformations”, AJNR 1990; 11:163-168; Mandai et al., “Direct thrombosis of aneurysms with cellulous acetate polymer: Part I: Results of thrombosis in experimental aneurysms”, J. Neurosurgery 1992; 77:497-500. These materials employ a different mechanism in forming synthetic emboli than do the cyanoacrylate materials. Cyanoacrylate glues are monomeric and rapidly polymerize upon contact with blood. On the other hand, precipitative materials are pre-polymerized chains that precipitate into an aggregate upon contact with blood.
Ideally, embolic material formed in situ is biocompatible, has a relatively short cure time from about a few seconds to a few minutes, exhibits minimal to moderate controllable swelling upon curing, exhibits long-term stability (preferably for at least ten years in vivo), and exhibits adequate mechanical properties, both in its pre- and post-cure state. For instance, such a material should have a relatively high viscosity before solidification or curing to facilitate safe and accurate delivery to the target site.
The hydrogel polymer materials described herein are also suitable for use in tissue bulking applications and more generally in inflatable devices suitable for implantation in a mammalian body, which devices are typically occlusive, such as those described variously in commonly owned copending U.S. patent application Ser. No. 10/461,853 to Stephens et al. entitled “Inflatable Implant”, filed Jun. 13, 2003, the entirety of which is herein incorporated by reference. Such devices may be delivered to a specific site in the body in a low profile form and expanded after placement to occlude or to support some region, vessel, or duct in the body. Examples of tissue bulking applications include the treatment of sphincter deficiencies exhibited by, e.g., gastroesophageal reflux disease (GERD), urinary and fecal incontinence, augmentation of soft tissue, and certain orthopedic indications. Many of the ideal characteristics of embolic materials cited above are shared for these applications.
The majority of the hydrogel polymer materials in the literature contain ester, polyurethane or silicone groups. Even though such hydrogel polymers are relatively easy to manufacture either by free radical, anionic, or cationic polymerizations, they tend to degrade in the body. For example, most hydrogels containing ester bonds can be hydrolyzed under physiological pH.
Despite the advances made in the science of hydrogel polymer compositions for use in medical applications, there remains a need in the art for hydrogel polymers having improved physical and mechanical properties for particular in vivo applications as described herein.